Spectroscopic study of the keto-enol equilibrium of N- aryldiacetylthioacetamides and their reactivity

Article abstract of DOI:10.1007/s10593-008-0051-3

An NMR study of the equilibrium between keto-enol tautomeric forms of N-aryl-diacetylthioacetamides enables us to estimate their population ratio in solvents of increasing polarity. An X-ray analysis confirmed the structure of the thermodynamically most s

Full text of DOI:10.1007/s10593-008-0051-3

Chemistry of Heterocyclic Compounds, Vol. 44, No. 3, 2008
SPECTROSCOPIC STUDY OF THE KETO-ENOL
EQUILIBRIUM OF N-ARYLDIACETYLTHIO-
ACETAMIDES AND THEIR REACTIVITY
B. Zaleska1, M. M. Burgieł1, and P. Serda2
An NMR study of the equilibrium between keto-enol tautomeric forms of N-aryl- diacetylthioacetamides
enables us to estimate their population ratio in solvents of increasing polarity. An X-ray analysis
confirmed the structure of the thermodynamically most stable tautomer. We presume that the course of
heterocyclization processes with N-aryldiacetylthioacetamides is affected by the structure of the
reacting tautomeric form. The treatment of N-aryldiacetylthioacetamides with oxalyl or bromoacetyl
bromides leads to thiazolidine derivatives. The reactivity of the 5-methylene group in the obtained
thiazolidin-4-one derivatives was investigated.
Keywords: anilide of 3-oxoalkanethioic acids, N-aryldiacetylthioacetamide, keto-enol equilibrium,
thiazolidin-4-one.
Recently it has been shown that anilides of 3-oxoalkanethioic acids are of particular interest due to their
capacity to react in different ways, depending on reagents and reaction conditions, both with dielectrophiles or
dinucleophiles, usually leading to heterocyclic compounds [1].
Modification of 3-oxoalkanethioic acid anilide in position 2 leads to novel interesting building blocks.
Due to this exceptionally polyfunctional reactivity such anilides have a wide synthetic potential [2–6]. Our
continual interest on this area encouraged us to undertake a study of the structure and reactivity of
N-aryldiacetylthioacetamides 1. Although keto-enol equilibrium of the derivatives of 3-oxoalkanethioic acid
amides has been studied [7], a spectroscopic study concerning equilibrium of the tautomeric forms of
2-substituted acid amides such as N-aryldiacetylthioacetamides 1 has not been described yet.
The introduction of an acetyl group at position 2 of N-arylacetylthioacetamide creates β,β'-dioxo-
(thioxo)system involving a ready movement of the CH proton along the intramolecular hydrogen bonds
(Scheme 1).
A perspective view of the molecule of compound 1a with the crystallographic atom numbering scheme
is shown in Fig. 1.
The 1H NMR spectra of compound 1a recorded in a polar solvent such as DMSO-d6 indicated the presence
of a signal of one OH group at 16.3 ppm, characteristic of the enol form A, NH amide proton at 12.00 ppm, and
one signal of two equivalent CH3 groups at 2.2 ppm (6H).
_________________________________________________________________________________________
1Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, 30-060 Kraków,
2
Poland; e-mail: zaleska@chemia.uj.edu.pl. Regional Laboratory of Physicochemical Analysis and Structural
Reasearch, 30-060 Kraków, Poland. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3,
pp. 452-459, March 2008. Original article submitted June 04, 2007. In revised form January 09, 2008.
0009-3122/08/4403-0349©2008 Springer Science+Business Media, Inc.
349

The13C NMR spectra of compound 1a clearly confirm the presence of only one form A with
characteristic signals of the C=S group carbon atom at 189.05 ppm and C=O carbon atoms in acetyl groups at
194.9 ppm; the sp3 carbons of CH3 groups appear as one signal at 23.3 ppm.
Scheme 1
H
O
O
S
O
N
H
H
S
O
H
O
H
N
S
N
O
H
Ar
Ar
Ar
B
A
C
O
H
O
H
O
H
O
H
N
S
N
S
Ar
Ar
E
D
The 1H and 13C NMR spectra of compound 1a indicated that the enol A is the dominating form in polar
solvents such as DMSO-d6. Compounds 1 enolize to form a stable intramolecular hydrogen bond between two
oxygen atoms of acetyl groups (Scheme 1).
1
All H and 13C NMR spectra of compound 1a recorded in solvents of lower polarity (chloroform,
benzene) show the presence of keto form B and other forms C, D, and E as well as enol form A. The relative
populations of tautomers B and C–E in solvents of different polarity was deduced from the signals of OH, NH,
CH3 groups in the 1H NMR spectra (Table).
The presence of keto form B in nonpolar solvent is demonstrated by a characteristic sp3 carbon shift at
1
80 ppm in the 13C NMR spectrum. This is confirmed by the singlet of CH (1H) at 5.7 ppm in the H NMR
spectrum and the singlet of NH amide proton at 10.9 ppm as well as of CH3 groups at 2.44 ppm (6H).
Fig. 1.
350

TABLE. Diagnostic chemical shifts of tautomeric forms A−E of compound
1a in solvents of various polarity and their relative population
δ, ppm
Solvent
CDCl3
ε
Form
%
OH
NH
8.9
CH3
CN
4.81
2.28
46.68
4.81
2.28
4.81
2.28
A
A
A
B
B
66
16.3
16.7
16.3
—
2.2
—
—
—
5.7
5.4
—
—
C6D6
66.5
100
7.2
8.5
1.9
DMSO-d6
CDCl3
C6D6
12.0
10.9
9.6
2.1
2.4
6.6
—
1.9
CDCl3
C6D6
C−E
C−E
26.3
26.8
16.4
16.9
9.7
1.6; 2.1
1.9; 1.7
10.9
The presence of the enol OH singlet at 16.4 ppm in CDCl3 and C6D6 solutions indicated the possible
existence of form C, being different from form A.
The generation of form C can be rationalized by the shift of the CH proton to the oxygen atom of the
acetyl group with the formation of an intramolecular hydrogen bond between the oxygen of OH group and the
sulfur atom of the thioamide group. Differences in the chemical shifts between hydrogen atoms of OH and NH
groups in tautomers A and C confirm that these atoms encounter a new steric situation.
In nonpolar solvents (benzene, chloroform) the NMR spectra display also signals of other tautomers: D
and E, interconverting rapidly with C on the NMR time scale.
In addition, the changes in the relative populations of tautomers A–D of compound 1a over the
temperature range of 120 K were measured in CDCl3. (Fig. 2).
The diagram shows that remarkable changes in the populations of tautomer A, B, and C and D (counted
together) are observed in the temperature range between 303-333 K, whereas in the range 213-03 K the changes
are insignificant.
For some years we have employed thioanilide derivatives as starting materials for the synthesis of
several biologically active heterocyclic compounds [8].
Fig. 2. Dependence of the population of tautomeric forms A, B and C, D on temperature.
The presence of several tautomeric forms of N-aryldiacetylthioacetamides 1 increased the number of
reactive centers and possible reaction routes. Due to the presence of forms A–C, the reaction of thioanilide 1
with dielectrophilic reagents may lead, depending on the dielectrophile and the reaction medium, to the
formation of different heterocyclic systems.
351

Besides the reactive centers typical of thioamide (electrophylic properties at the thiocarbonyl carbon
atom and nucleophilic at thiocarbonyl sulfur and nitrogen atoms), N-aryldiacetylthioacetamides 1 have an
additional nucleophilic position at oxygen of one of the acetyl groups. Due to this exceptionally polyfunctional
character of compound 1 [9], its reactivity may have a wide synthetic potential.
Moreover, N-aryldiacetylthioacetamides 1 bearing the acetyl group in position 2 may also lose one of
the acetyl substituents during the substitution reactions.
The purpose of this paper is to describe our investigations on the participation of appropriate tautomeric
forms A–C of N-aryldiacetylthio- acetamides 1 in reactions with alkylating and acylating agents in nonpolar
medium such as chloroform or toluene.
In our previous investigation [10], with such double acylating reagent as phosgene, 1,3-oxazine
derivatives 2 were isolated as the result of O- and N-acylation of N-aryldiacetylthioacetamides 1. However, a
different course of reaction was observed when oxalyl chloride was used. Regiospecific S- and N-thioamide
acylation reaction of compound 1 took place (Scheme 2).
Scheme 2
O
S
N
Ar
O
H
COCl2
toluene, r.t.
BrCH2COBr
1 a–f
[10, 11]
80
°C, toluene
(COCl)2
toluene, r.t.
O
N
O
S
S
O
S
O
O
H
N
O
Ar
Ar
4 a, b
N
O
O
O
2 a–f
[10]
Ar
3 a–d
a Ar = Ph, b Ar = p-ClC6H4, c Ar = p-BrC6H4, d Ar = p-IC6H4, e Ar = α-C10H7,
f Ar = β-C10H7
Spectral analysis of the product obtained as a result of heterocyclization with oxalyl chloride confirmed
the structure of thiazolidin-4,5-dione derivatives 3.
The treatment of compound 1 with bromoacetylbromide in boiling toluene leads to the thiazolidin-4-one
derivatives 4. This heterocyclization proceeds as the electrophilic substitution−condensation with participation
of the sulfur and nitrogen atoms of a thioamide group with elimination of one acetyl group. Products 4 are
assigned the structure of thiazolidin-4-one derivatives on the basis of their spectral data and elemental analysis.
1
In the 13C NMR and H NMR spectra of obtained compounds 4 the specific signals of CH2 as well as
CH= groups confirm that compounds 4 exist only in one geometric configuration. On the basis of this
assumption the Z-configuration is proposed (Scheme 2).
352

The bromination reaction of thiazolidin-4-ones 4a,b leads to products 5a,b. The treatment of product 5a
with morpholine in boiling ethanol leads to a mixture of two interesting derivatives: red crystalline product 7
insoluble in ethanol and colorless compound 6 with good solubility in ethanol (Scheme 3).
Scheme 3
O
Br
S
Br2
CHCl
4a,b
C,
0°
H
N
3
O
Ar
O
5a,b
N
H
(Ar = Ph)
O
ethanol
Ph
O
O
O
N
S
O
N
S
S
H
N
O
N
O
Ph
Ph
6
7
The above results of the reactions suggest that the participation of the C enol form in the process of
heterocyclic construction of compounds 3 and 4 is predominant.
On the other hand, from a mechanistic point of view the synthesis of 1,3-oxazine system with phosgene
confirms a bielectrophilic attack on the oxygen and the nitrogen (amide) of enol form A. When a reactant
different than phosgene was used, in the first step, an intermediate seven-membered system of thiazepine can be
formed, but Dimroth rearrangement leads to thermodynamically more stable five-membered system.
The heterocyclization process of N-aryldiacetylthioacetamides 1 depends mostly on the medium
polarity, population of the tautomers, as well as stability of intermediate systems.
EXPERIMENTAL
Melting points were determined on an electrothermal IA9000 digital mp apparatus and are uncorrected.
IR spectra were obtained on a Bruker IFS 48 spectrometer (KBr). 1H and 13C NMR spectra were recorded with a
Bruker AMX 500 (500 and 125 MHz, respectively) or AVANCE II 300 (300 and 75MHz, respectively) NMR
spectrometer in CDCl3 at room temperature. Mass spectra (EI) were registered with Finnigan 95JS instrument
(70 eV). Yields are given for pure products.
Compounds 1a-f and 2a-f were prepared according to [11] and [10], respectively.
X-Ray investigation. X-ray analysis of compound 1a was carried out to determine its structure in the
solid state. Compound 1a with formula C12H13NO2S crystallizes (from benzene) in the monoclinic system, space
group P21/a, with unit cell parameters a = 948.54(2), b = 1619.18(2), c = 987.69(2) pm, β = 92.473(1)º,
V = 515.54(5)⋅106 pm3, Z = 4. A total of 12 944 reflections (the whole sphere) were collected up to θ = 27.51º
and merged to give 3454 independent reflections (R(int) = 0.0251) on a single-crystal sample (size 0.35×0.30×0.15
mm) using a KappaCCD diffractometer and MoKα radiation. The structure was solved by direct methods and
353

refined by the full-matrix least squares method on F2 using the SHELX97 program system. All hydrogen atoms
were located on a difference Fourier map of electron density. Final R indices for I>2σ(I) were equal to
R1 = 0.0506, wR2 = 0.1434, and R1 = 0.0650, wR2 = 0.1534 for all data. The final difference Fourier map of
electron density was featureless with the largest peak and hole at 0.277 and -0.206 e⋅Å-3, respectively. The
structural data have been deposited at the Cambridge Crystallographic Data Centre under the reference number
CCDC 672481.
It can be seen that the crystal structure includes solvent molecules, two per unit cell. The pseudo-ring
C(3)−C(4)−O(8)−H(8)−O(5)−C(7) is quite flat: no atom deviates from the least-squares plane by more than
0.005 Å. Both oxygen atoms – O(5) and O(8) – share one hydrogen atom, thus forming a very short hydrogen
bond (D−A distance 2.433(3) Å, D−H···A angle 151.2(2)º) with O(5) and O(8) being in turn donor or acceptor.
This results in a disordered position of the hydrogen atom (either bound to O(5) or O(8) with occupancies
converging to 0.3(1)/0.7(1), respectively. Also both oxygens O(5) and O(8) seem to be disordered, which can be
inferred from their rather high atomic displacement parameters. However, no precise disorder model could be
found, as the coordinates of these atoms are continuously spread rather than limited to two or three definite
values. The consequence of this disorder includes somewhat higher R factors. The packing of the crystal
structure is dominated by van der Waals interactions, with no strong intermolecular hydrogen bonds.
3-Aryl-2-(diacetylmethylidene)-1,3-thiazolidine-4,5-diones 3a–d (General Method). To 0.01 mol of
compound 1 dissolved in 50 cm3 of dry toluene, oxalyl chloride (1.26 g, 0.01 mol) dissolved in 20 cm3 of dry toluene
was added dropwise, and the mixture was stirred at room temperature. After the reaction was completed and
evolution of gaseous HCl stopped, the yellow precipitate was filtered off.
2-(Diacetylmethylidene)-3-phenyl-1,3-thiazolidine-4,5-dione (3a). Yellow crystals from toluene−hexane
mixture (1:1), yield 60%; mp 214°C. IR, ν, cm−1: 1740 (C=O), 1720 (C=O), 1680 (C=O). 1H NMR spectrum, δ,
ppm: 1.8 (3H, s, CH3); 2.15 (3H, s, CH3); 7.50-7.78 (5H, m, aromatic protons). 13C NMR spectrum, δ, ppm:
32.67 (CH3CO); 29.16 (CH3CO); 122.29 (C=); 183.63−200.19 (C=O); 155.93 (S−C−N). Found, %: C 58.02;
H 3.78; N 4.87; S 11.12. C14H11NO4S. Calculated, %: C 58.12; H 3.83; N 4.84; S 11.08.
3-(p-Chlorophenyl)-2-(diacetylmethylidene)-1,3-thiazolidine-4,5-dione (3b). Yellow crystals from
toluene−hexane mixture (1:1), yield 70%; mp 175°C. IR, ν, cm−1: 1750 (C=O), 1725 (C=O), 1675 (C=O).
1H NMR spectrum, δ, ppm: 1.9 (3H, s, CH3); 2.15 (3H, s, CH3); 7.07-7.68 (4H, m, aromatic protons). 13C NMR
spectrum, δ, ppm: 30.9 (CH3−CO); 31.3 (CH3−CO); 122.2 (C=); 189.63-200.19 (C=O); 157.03 (S−C−N). Found,
%: C 51.95; H 2.98; N 4.33; S 9.89. C14H10ClNO4S. Calculated, %: C 51.94; H 3.11; N 4.33; S 9.90.
3-(p-Bromophenyl)-2-(diacetylmethylidene)-1,3-thiazolidine-4,5-dione (3c). Yellow crystals from
toluene−hexane mixture (1:1), yield 60%; mp 180°C. IR, ν, cm−1: 1750 (C=O), 1720 (C=O), 1685 (C=O).
1H NMR spectrum, δ, ppm: 1.95 (3H, s, CH3); 2.10 (3H, s, CH3); 7.06−7.56 (4H, m, aromatic protons).
13C NMR spectrum, δ, ppm: 31.20 (CH3−CO); 29.23 (CH3−CO); 185.63−200.19 (C=O); 155.98 (S−C−N); 122
(C=). Found, %: C 45.44; H 2.45; N 3.81; S 8.65. C14H10BrNO4S. Calculated, %: C 45.67; H 2.74; N 3.80; S 8.71.
2-(Diacetylmethylidene)-3-(p-iodophenyl)-1,3-thiazolidine-4,5-dione (3d). Yellow crystals from
toluene−hexane mixture (1:1), yield 50%; mp 160°C. IR, ν, cm−1: 1740 (C=O), 1720 (C=O), 1685 (C=O).
1H NMR spectrum, δ, ppm: 1.9 (3H, s, CH3); 2.54 (3H, s, CH3); 7.06−7.56 (4H, m, aromatic protons). 13C NMR
spectrum, δ, ppm: 30.9 (CH3−CO); 29.8 (CH3−CO); 185.63-200.19 (C=O); 152.6 (S−C−N); 119 (C=). Found, %:
C 40.10; H 2.39; N 3.28; S 7.25. C14H10INO4S. Calculated, %: C 40.50; H 2.43; N 3.37; S 7.72.
2-Acetylmethylidene-3-aryl-1,3-thiazolidin-4-ones 4a,b (General Method). To 0.01 mol of
compound 3 dissolved in 50 cm3 of hot (80°C) dry toluene, (1.67 g, 0.01 mol) of ethyl bromoacetate was added
dropwise. The mixture was stirred at room temperature for 2 h. The colorless precipitate was filtered off and
crystallized from chloroform.
2-Acetylmethylidene-3-phenyl-1,3-thiazolidin-4-one (4a). Crystals from chloroform, yield 82%; mp
1
202-204°C. IR, ν, cm−1: 1720 (C=O), 1660 (C=O). H NMR, spectrum, δ, ppm: 2.01 (3H, s, CH3); 3.85 (2H, s,
CH2); 5.10 (1H, s, CH=); 7.2-7.5 (5H, m, aromatic protons). 13C NMR spectrum, δ, ppm: 31.80 (CH3−CO);
354

40.23 (CH2); 105.46 (CH=); 145.39 (S−C−N); 172.40 (C=O); 195.91 (C=O). Mass spectrum, m/z (Irel, %): 233
[M]+; 218 [M+−CH3] (74); 190 [M+−CH3CO] (100). Found, %: C 61.33; H 4.66; N 5.83. C12H11NO2S. Calculated,
%: C 61.78; H 4.75; N 6.00.
2-Acetylmethylidene-3-(p-chlorophenyl)-1,3-thiazolidin-4-one (4b). Crystals from chloroform, yield
1
50%; mp 202−204°C. IR, ν, cm−1: 723 (C=O), 1642 (C=O). H NMR spectrum, δ, ppm: 2.21 (3H, s, CH3); 3.9
13
(2H, s, CH2); 5.52 (1H, s, CH=); 7.3−7.7 (5H, m, aromatic protons). C NMR, δ, ppm: 31.79 (CH3CO); 40.23
(CH2); 101.14 (CH=); 159.60 (S−C−N); 172.40 (C=O); 196.91 (C=O). Mass spectrum, m/z (I rel, %): 267
[M]+(88); 252 [M+−CH3] (95); 224 [M+−CH3CO] (100). Found %: C 53.63; H 3.73; N 5.03. C12H10ClNO2S.
Calculated, %: C 53.83; H 3.76; N 5.23.
2-Acetylmethylidene-5-bromo-3-phenyl-1,3-thiazolidin-4-one (5a). Compound 4a (2.3 g, 0.01 mol)
dissolved in 20 cm3 CHCl3 was cooled in ice bath, and bromine (0.8 g, 0.01 mol) dissolved in 20 cm3 CHCl3 was
added dropwise. After 1 h the solvent was removed. Amorphous precipitate was very difficult to purify
(decomposition during chromatography).
2-Acetylmethylidene-5-bromo-3-(p-chlorophenyl)-1,3-thiazolidin-4-one (5b) was prepared similarly
from 4b. Melting points of crude precipitates 5a 178°C, 5b 180°C.
IR spectra, ν, cm−1: 5a − 1720 (C=O), 1643 (C=O), amide 1521 (C=C); 5b − 1741 (C=O), acetyl group 1652
(C=O), amide group 1521 (C=C).
2-Acetylmethylidene-5-morpholino-3-phenyl-1,3-thiazolidin-4-one (6). The mixture of compound 5a
(2.0 g, 0.01 mol) dissolved in ethanol and morpholine (0.87 g, 0.01 mol) was refluxed for 1–2 h. Red needle
product 7a was filtered off from hot solution. After cooling colorless precipitate 6a was filtered off. Yield 30%.
1
IR spectrum, ν, cm−1: 1720 (C=O), 1643 (C=O), 1521 (C=C). H NMR spectrum, δ, ppm: 2.07 (3H, s, CH3);
2.59 (2H, m, NCH2); 2.88 (2H, m, NCH2); 3.78 (4H, m, OCH2); 5.26 (1H, s, H-5); 5.58 (1H, s, CH=); 7.58-7.23
(5H, m, aromatic protons). 13C NMR spectrum, δ, ppm: 30.78 (CH3CO); 49.01 (NCH2); 66.52 (OCH2); 72.31,
102.48 (CH=); 156.46 (S−C−N); 171.04 (C=O); 196.24 (C=O). Found, %: C 59.78; H 5.43; N 8.45.
C16H18N2O3. Calculated, %: C 60.06; H 5.70; N 8.80.
2-(Acetylmethylidene)-5-E-(2-acetylmethylidene-4-oxo-3-phenyl-1,3-thiazolidinyl-5-ylidene)-
1,3-thiazolidin-4-one (7). Yield 21%; mp more than 370°C. IR spectrum, ν, cm–1: 1705 (C=O), 1649 (C=O),
1
1523 (C=C). H NMR spectrum, δ, ppm: 2.09 (6H, s, 2CH3); 5.70 (2H, s, =CH); 7.48–7.67 (10H, m, aromatic
protons). Found, %: C 61.98; H 4.01; N 5.80. C24H18N2O4S2. Calculated, %: C 62.32; H 3.92; N 6.06.
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